Dry powder inhalers

ABSTRACT

Dry powder inhalers and dry powder inhaler storage cassettes including a compartment housing an elongate carrier preloaded with a plurality of doses of finely divided powder comprising a biologically active substance, the compartment being configured such that said preloaded doses are sealed within said compartment and such that the carrier may be advanced from the compartment to the chamber through an exit provided with a moisture barrier sealing system, wherein the moisture barrier sealing system is configured and arranged such that it is relaxable during advancement of the carrier, said sealing system being in sealing configuration prior to an advancement of the carrier, relaxed upon an advancement of the carrier and returned to its sealing configuration at the latest after release of the powder associated with said area of the carrier.

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.15/276,521, filed Sep. 26, 2016, which is a continuation of U.S.application Ser. No. 14/622,617, filed Feb. 13, 2015, which iscontinuation of U.S. application Ser. No. 13/320,762, filed Jan. 13,2012, which is the U.S. national phase of International Application No.PCT/US2010/035280, filed May 18, 2010, which claims the benefit of U.S.Provisional Application No. 61/179,220, filed May 18, 2009. Thedisclosures of each of these applications are hereby incorporated hereinby reference.

FIELD

This invention relates to dry powder inhalers as well as to cassettes,such as removable and/or re-fill supply cassettes, for use in dry powderinhalers.

BACKGROUND

Asthma and other respiratory diseases have long been treated by theinhalation of appropriate medicaments. For many years the two mostwidely used and convenient choices of treatment have been the inhalationof medicament from a drug solution or suspension in a pressurisedmetered dose inhaler (pMDI), or inhalation of powdered drug, generallyadmixed with an excipient, from a dry powder inhaler (DPI). Followingstrong concern about the link between depletion of the earth's ozonelayer and chlorofluorocarbon (CFC) emissions, the use of these materialsin pressurised inhalers is being phased out and interest in DPI systemshas been stimulated.

Quite a number of DPI systems or components for DPI systems have beendescribed including those described in, for example, GB 2242134 (Davieset al.), U.S. Pat. No. 5,192,548 (Velasquez et al.), U.S. Pat. No.5,619,984 (Hodson et al.), U.S. Pat. No. 5,657,748 (Braithwaite), WO98/41255 (Jennings et al.), WO 01/21238 (Seppala), and US 2006/0081246(Goede et al.).

In practice most DPIs use either bulk powder reservoirs or individualpre-measured doses sealed within individual containers in the form ofcapsules or blisters, such as blister packs and blister strips.

There are, however, problems associated with accurately metering ameasured small quantity (e.g., 500 micrograms or less) of powder from abulk reservoir within an inhaler. With many drugs, e.g., potent drugs,this introduces the necessity to add excipients, such as lactose powder,to significantly increase the quantity of powder to be metered. Suchexcipients are however generally undesirable as they can pose subsequentpowder deagglomeration problems and can cause dryness and other unwantedeffects in the patient's mouth.

Furthermore, ingress of moisture (ambient moisture and/or moisture froma patient's breath e.g., inadvertently exhaled into the inhaler) intoe.g., the bulk powder reservoir can pose a serious problem. Manybiologically active substances, such as medicaments, delivered byinhalation are susceptible to physical or chemical change and/ordegradation in the presence of moisture vapor. For example, the powderedparticles may re-crystallize in the presence of adsorbed moisture vapor,which may lead to an effective increase in the median particle size ofthe powdered material, which in turn may lead to reduced penetration ofthe particles into relevant delivery sites in the lung, e.g., the lowerairway passages in the lung.

DPIs where the powder supply, e.g., powdered medicament, is provided inthe form of capsules or blisters generally have somewhat better moistureprotection, due to the fact that each individual dose is sealed off,where typically a dose on a carrier component is covered and sealed witha lid component. The manufacturing of such capsules, blister packs orblister strips, including accurately metered, small quantities of powderper capsule/blister for use in a DPI, can be difficult and/or quiteexpensive. Furthermore, DPIs using such a powder supply normally requirecomplex mechanisms for opening the individually sealed capsules orblisters (e.g., mechanisms for peeling the lid off, puncturing thecapsule/blister, etc.).

SUMMARY

According to one aspect of the present invention there is provided a drypowder inhalation device comprising: a chamber; a patient port incommunication with said chamber; a compartment housing an elongatecarrier preloaded with a plurality of doses of finely divided powdercomprising a biologically active substance, said powder being releasablyretained on a surface of the carrier, said compartment being configuredsuch that said preloaded doses are sealed within said compartment andsuch that the carrier may be advanced from the compartment to thechamber through an exit provided with a moisture barrier sealing system;an advancement mechanism for advancing a portion of the carrier from thecompartment to within the chamber so that the powder associated with anadvanced area of the carrier can be released from the carrier forinhalation by the patient through the patient port; wherein the moisturebarrier sealing system is configured and arranged such that it isrelaxable during advancement of the carrier, said sealing system beingin sealing configuration prior to an advancement of the carrier, relaxedupon an advancement of the carrier and returned to its sealingconfiguration at the latest after release of the powder associated withsaid area of the carrier.

Such a dry powder inhalation device is advantageous in that it provideseffective protection against moisture and moisture ingress, while at thesame time allowing the provision of a carrier preloaded with finelydivided powder to provide a plurality of doses, without the necessity ofhaving to provide individual doses and to hermetically seal each ofthese individual doses. In other words the finely divided powder doesnot need to be pre-metered into doses and the carrier need not becovered and sealed with a lid component, such as a foil lid layercomponent, since the moisture barrier sealing system advantageouslyreturns to its sealing configuration at the latest after release of thepowder associated with the advanced area of the carrier prior toadvancement of the next portion of the carrier.

Protection against moisture and moisture ingress can be furtherfacilitated in certain favorable embodiments in which the moisturebarrier sealing system is configured and arranged such that the sealingsystem is returned to its sealing configuration at least prior torelease of the powder associated with said area of the carrier.Protection against moisture and moisture ingress can be yet furtherenhanced in certain particularly favorable embodiments in which themoisture barrier sealing system is configured and arranged such that thesealing system is returned to its sealing configuration upon cessationof advancement of the carrier. The latter mentioned embodiments areparticularly advantageous in that the moisture barrier sealing systemmay generally and advantageously work in a “dead man's handle” mannerwherein a seal is applied to the supply compartment exit whenever thecarrier is not being advanced, i.e. the moisture barrier sealing systemgenerally operates such that it returns automatically to its sealingconfiguration as soon as advancement of the carrier stops. (Under thephrases such as “sealing system returns” or “sealing system is returned”as used herein it will be understood that the sealing system may returnon its own accord or through the action of a separatemechanism/element.)

The compartment may be favorably provided within a cassette that isreversibly removable from the dry powder inhaler. Such a cassette can bein itself advantageous in that it can be used as a powder storage and/orsupply unit, e.g., an original supply unit and/or a re-fill supply unit,for a dry powder inhaler.

According to a second aspect of the present invention there is provideda device for storing dry powder for use in a dry powder inhaler, saiddevice provided in the form of a cassette comprising: a compartmenthousing an elongate carrier preloaded with a plurality of doses offinely divided powder comprising a biologically active substance, saidpowder being releasably retained on a surface of the carrier; saidcompartment being configured such that preloaded doses are sealed withinsaid compartment and such that the carrier may be advanced from thecompartment to the outside of the compartment through an exit providedwith a moisture barrier sealing system, wherein said device isconfigured and arranged such that during use in a dry powder inhalerwherein a portion of the carrier is advanced so that the powderassociated with an advanced area can be released from the carrier forinhalation by the patient through the patient port of the inhaler, themoisture barrier sealing system is relaxable during advancement of thecarrier, so that said sealing system is in sealing configuration priorto an advancement of the carrier, will relax upon an advancement of thecarrier and will be returned to its sealing configuration at the latestafter release of the powder associated with said area of carrier.

In certain favorable embodiments of devices in accordance with aspectsdescribed above it has been found particularly advantageous to have thearea of the carrier, which has been advanced into the chamber so thatthe powder associated with said area of the carrier can be released fromthe carrier for inhalation by the patient through the patient port(referred to in the following simply as the “dose-release area”) beclamped at its “ends” during release of the powder associated with saidarea of the carrier. This double-clamping has been found to beadvantageous in reducing and/or preventing powder from other areas ofthe carrier, either behind or ahead of the dose-release area within thechamber, from being dislodged from the carrier when the powder in thedose-release area is released, and thus minimizing and/or preventingbuild-up of stray powder within the inhaler and correspondingly allowingfor improved reproducibility of the emitted dose. Accordingly in certainembodiments, devices may favorably further comprise a first clampingsystem and a second clamping system, wherein the systems are configuredand arranged such that they are moved into a clamping configuration atleast prior to release of the powder associated with the dose-releasearea, so that the dose-release area will be clamped between the firstand the second clamping systems during release of the powder associatedwith the dose-release area. In other words the dose-release area ispositioned between two clamping systems and clamped by the two systemsprior to release of the powder. In other embodiments, e.g., where themoisture barrier sealing system is arranged and configured to return toits sealing configuration at least prior to release of the powderassociated with the dose-release area, the moisture barrier sealingsystem may favorably also act as a clamping system. Such embodiments maythus favorably include a clamping system in addition to the moisturebarrier sealing system, said clamping system being configured andarranged such that it is moved into a clamping configuration at leastprior to release of the powder associated with the dose-release area andwherein said clamping system and said moisture barrier sealing systemare configured and arranged relative to one another such that said areaof the carrier will be clamped between the clamping system and themoisture barrier sealing system during release of the powder associatedwith the dose-release area. In other words the dose-release area ispositioned between the moisture barrier sealing system and a secondclamping system and clamped by the two systems prior to release of thepowder associated with the dose-release area.

A double-clamping can also be advantageously used in dry powder inhalerswhich do not make use of a moisture-barrier sealing system in accordancewith the aforementioned first and second aspects. Accordingly there isprovided in a third aspect of the present invention a dry powderinhalation device comprising: a chamber; a patient port in communicationwith said chamber; an elongate carrier preloaded with a plurality ofdoses of finely divided powder comprising a biologically activesubstance, said powder being releasably retained on a surface of thecarrier; an advancement mechanism for advancing a portion of the carrierto within the chamber so that the powder associated with an advancedarea of the carrier can be released from the carrier for inhalation bythe patient through the patient port; and a first clamping system and asecond clamping system, wherein the first and second clamping systemsare configured and arranged such that they are moved into a clampingconfiguration at least prior to release of the powder associated withsaid area of the carrier, so that said area of the carrier will beclamped between the first and the second clamping systems during releaseof the powder associated with said area of the carrier.

Devices in accordance with the second aspect described herein, e.g.,cassettes, for storing powder for use in a dry powder inhaler may alsocomprise an appropriate clamping system or clamping systems.

Clamping systems may also be provided in storage devices that do notinclude a moisture-barrier sealing system in accordance with theaforementioned first and second aspects. Thus in a fourth aspect of thepresent invention there is provided a device for storing dry powder foruse in a dry powder inhaler, said device comprising: an elongate carrierpreloaded with a plurality of doses of finely divided powder comprisinga biologically active substance, said powder being releasably retainedon a surface of the carrier; a first clamping system and a secondclamping system, wherein said device is configured and arranged suchthat during use in a dry powder inhaler wherein a portion of the carrieris advanced so that the powder associated with an advanced area can bereleased from the carrier for inhalation by the patient through thepatient port of the inhaler, the first and second clamping systems willbe moved into a clamping configuration at least prior to release of thepowder associated with said area of the carrier, so that said area ofthe carrier will be clamped between the first and the second clampingsystems during release of the powder associated with said area of thecarrier.

Dependent claims define further embodiments of the invention.

BRIEF DESCRIPTION OF DRAWINGS

The invention will now be described with reference to the accompanyingdrawings in which:

FIGS. 1 to 3 represent partial cross sectional illustrations of anexemplary dry powder inhaler in its closed position, a partially openposition and its fully opened position, respectively.

FIGS. 4 to 7 represent cross sectional illustrations of a particularregion of the exemplary dry powder inhaler in its closed position, apartially open position and its fully opened position, as well as atactuation, respectively.

FIGS. 8 to 11 represent partial cross-sectional illustrations of anadditional particular region of the exemplary dry power inhaler in itsclosed position, a partially open position, a yet further, but not fullyopened position and its fully opened position, respectively.

FIG. 12 represents a partial cross-sectional illustration of anadditional particular region of the exemplary dry power inhaler in itssealed position after stopping opening mid-way.

FIG. 13 represents an isometric view of part of the compartment of theexemplary dry powder inhaler, showing the supply spool and the frictionbrake.

FIG. 14 represents a partial cross sectional illustration of the regionof the supply spool with the elongate carrier wound on it, plus theouter component of the friction brake.

DETAILED DESCRIPTION

It is to be understood that the present invention covers allcombinations of particular, suitable, desirable, favorable, advantageousand preferred aspects of the invention described herein.

FIGS. 1 to 3 represent partial cross sectional illustrations of anexemplary dry powder inhaler (10) in its closed position, a partiallyopen position and its fully opened position, respectively. The inhaler(10) includes a chamber (200) and a patient port, in particular in theform of a mouthpiece (300), in communication with said chamber. Thepatient port is not visible in FIG. 1, because in the closed position ofthe illustrated inhaler the mouthpiece is covered by a cover (301). Onlywhen the user opens the inhaler for use, i.e. opens the mouthpiece-cover(301) as shown in FIGS. 2 and 3, does the patient port (300) becomevisible. The inhaler (10) also includes an elongate carrier (100)preloaded with finely divided powder comprising a biologically activesubstance (not visible).

The elongate carrier can be provided in a variety of forms, such as atape, web, belt or cord. Desirably the carrier is provided in the formof a tape or a web. The elongate carrier may have any ratio of length towidth but said ratio is generally greater than 5 to 1, usually greaterthan 10 to 1, more particularly from about 100:1 to about 1000:1. Theelongate carrier may typically have a width of 5 mm to 20 mm, e.g., 10mm. Its thickness may typically be from 75 microns to 500 microns,particularly from 100 microns to 250 microns, more particularly fromabout 120 microns to 175 microns. If desired, the elongate carrier maybe provided with a lid component, for example to cover and/or seal offindividual doses. However, such covering and sealing is generally notneeded in embodiments in accordance with certain aspects of theinvention described herein, and thus accordingly favorably the carrierdoes not comprise a lid component covering and sealing off individualdoses.

The powder comprising a biologically active substance, typically amedicament, is releasably retained on a surface of the carrier. Thepowder may be retained on the carrier by attraction forces, such aselectrostatic attraction, van der Waals forces, physical attraction;mechanical binding; and/or wedging. Alternatively powder may be retainedon the carrier by covering the powder using a lid component; however asindicated supra it is not desirable (nor necessary in accordance withcertain aspects of the invention described herein) to use a lidcomponent. To facilitate favorable release characteristics, it isdesirable not to retain the powder on the carrier via adhesives orglues. The aforesaid expression “mechanical binding” generally refers topowder particles being held onto the carrier by intrinsic mechanicalmeans of the carrier material, e.g., within the entanglement of fibersof a nonwoven web. The expression “wedging” generally refers to loadingpowder particles within/into particular structures of the elongatecarrier (e.g., micro-depressions provided in a plastic elongate carrieror porous spaces of a nonwoven elongate carrier). One or more surfacesof the carrier and optionally the interior of the carrier may beconfigured to assist in retaining the particles of powder.

A carrier may be constructed from one or more of a wide range of naturaland synthetic materials e.g., polyethylene, polypropylene, polyestere.g., polyethylene terephthalate, polytetrafluoroethylene or aco-polymer thereof, ethylene vinyl alcohol, or cellulose. The materialsmay be in the form of non-woven fibrous materials, loose weave materialsor fabrics, materials having a surface pile, films, microporousmaterials, microgrooved materials, cords of twisted fibers, or any othersuitable material or composites of more than one material. Desirably acarrier is constructed of a material or a material composite where smallsurface depressions, dimples, grooves, recesses, interstices, aperturesor embossed surface structures having a typical size of equal to or lessthan 500 microns in either depth or height and of greater than 0.1microns in at least one other dimension are provided to help to retainthe particles of powder. Various materials for carriers as well asparticular forms of carriers suitable for use herein are disclosed inU.S. Pat. No. 5,619,984 (Hodson et al.), the contents of said patent inits entirety being incorporated herein by reference.

The form of the elongate carrier can in part play a role in the storageformat. For example a cord may be conveniently stored as a coil or woundon a spool, while a tape or web may be for example folded or wound on aspool. Generally it is favorable for an elongate carrier to be wound ona spool.

As shown in the exemplary embodiment illustrated in FIGS. 1 to 3, thecarrier (100) may be stored initially on a supply spool (102) andadvanced onto an uptake spool (104) during use of the inhaler. Duringuse of an inhaler, in general, a portion of the carrier is advanced towithin the chamber so that the powder associated with an advanced areaof the carrier can be and is, upon actuation, released from the carrierfor inhalation by the patient through the patient port.

For ease of illustration, as well as of viewing, a total length ofcarrier shorter than typical has been shown in FIGS. 1 to 3. The carrier(100), with its preloaded finely divided powder providing a plurality ofdoses, is housed within a compartment (105), with the compartment beingconfigured so that the preloaded doses are sealed within the compartmentand such that the carrier may be advanced from the compartment to thechamber (200) through an exit (not quite visible in FIGS. 1 to 3)provided with a moisture barrier sealing system (110).

This may be better appreciated in FIGS. 4 to 6, which show across-sectional, detailed view of the region about the compartment exitand the lower portion of the chamber of the exemplary inhaler, atpositions with the mouthpiece cover closed (prior to an advancement),partially open (during advancement) and fully open (prior to powderrelease) respectively. In the Figures the compartment (105) is to theleft, and the compartment wall (106) is provided with an exit (107),best seen in FIG. 5, through which the carrier (100) is advanced. In theclosed position shown in FIG. 4, it can be seen that the moisturebarrier sealing system (110) is in a sealing configuration; inparticular a seal (111) is pushing against the carrier and the outersurface (106 a) of the compartment wall (106), thereby sealing over theexit (107) of the compartment. As shown in FIG. 5—showing a partiallyopen position—as the user opens the mouthpiece cover, the sealing systemrelaxes allowing the seal (111) to disengage from the compartment outerwall surface (106 a) and the carrier (100) to advance (discussed in moredetail infra). When the user has fully opened the cover, or better said,when advancement of the carrier has been completed by the user, andprior to release of powder associated with said advanced area of thecarrier, the sealing system returns to its sealing configuration where,as can be seen in FIG. 6, the seal (111) is once again clamped againstthe carrier (100) and the outer surface (106 a) of the wall (106) of thecompartment (105), thereby sealing over the exit (107) of thecompartment.

In favorable embodiments the moisture barrier sealing system isconfigured and arranged such that the sealing system is returned to itssealing configuration at least prior to release of the powder associatedwith the dose-release area of the carrier.

The moisture barrier sealing system suitably comprises a seal or seals.The seal(s) typically is that component of the system which seals overthe exit of the compartment when the system is in its sealingconfiguration. Suitable materials for a moisture barrier seal may have aShore A hardness value equal to or less than 75, in particular equal toor less than 65 (as determined by ASTM test number D2249). Suitablematerials for a moisture barrier seal may have a Shore A hardness valueequal to or greater than 35, in particular equal to or greater than 45(as determined by ASTM test number D2249). Favorably such a seal isresilient, and thus most desirably comprises an elastomeric material,such as Silicone rubber. Preferably a thermoplastic elastomer is used,e.g., EPDM and polypropylene blends, such as those available under thetrade designation SANTOPRENE, or styrene-isoprene copolymers, such asthose available under the trade designation KRATON. Such elastomers maybe co-molded with another component of the device (such as a pivotingcomponent discussed infra), and may be selected to have hardness andcompliance to provide for optimal sealing when the moisture barriersealing system is in its sealing configuration. Elastomeric materials orco-molded surface components may be provided on any or all of therelevant sealing surfaces of the device (e.g., on all the surfaces thatcontact the carrier and that form part of the moisture barrier sealingsystem). Any or all of the seal or seals may have a molded profile toallow for the thickness of the carrier, e.g., the seal may have a slightrecess for the carrier's thickness to sit in. Preferably such a recesswould be slightly shallower than the thickness of the carrier.

The compliance needed in the seal material is relative, and will dependon several factors. In particular, the degree of precision in the(manufactured) parts that determine how precisely the seal and thecompartment exit mate with each other, the thickness of the seal, thearea of the seal that makes contact with the compartment exit, theresilience of the carrier, the use of springs and their force, and thedegree of moisture protection required may all influence the selectionof an optimal seal material. In certain instances the seal andcompartment may mate sufficiently well so that a non-elastomeric sealmaterial may provide satisfactory sealing and protection from moistureingress. Suitable non-elastomeric seal materials include plastics, suchas polyethylene, polypropylene, and acrylonitrile-butadiene-styrene(ABS). In one embodiment the seal and another component of the device(such as a pivoting component) may be integrally formed from a singleplastic material. In another embodiment, said device component (e.g., apivoting component) may be made of any resilient thermoplastic, such asABS, and an elastomeric seal may be placed or molded onto saidcomponent.

The compartment may advantageously house a desiccator. The desiccatormay be favorably provided in the form of a cartridge containing a waterand/or moisture adsorbing material. Such water and/or moisture adsorbingmaterials are well known and may include activated alumina, aerogel,benzophenone, bentonite clay, calcium chloride, calcium hydride, calciumsulfate, copper (II) sulfate, lithium chloride, lithium bromide,magnesium nitrate, magnesium sulfate, magnesium perchlorate, molecularsieve(s), potassium carbonate, silica gel, sodium chlorate, sodiumsulfate, sodium benzophenone. The use of such a desiccator can be easilyseen in the illustrations of the exemplary embodiment in FIGS. 1 to 3,as component 108.

Favorably, the compartment is configured so that the relative humiditywithin the compartment is maintained at a level of about 75% or lower,more favorably 65% or lower, most favorably 60% or lower, over a periodof thirty (30) days. Thirty days is a typical duration of intendedpatient use of a device described herein (i.e. after the patient hasremoved the device from any secondary packaging, such as a sealed pouch,and up to and including the last dose taken). For example, for a devicecontaining 120 doses where two doses would be taken twice a day, theintended duration of use would be thirty 30 days. In certain instances,it has been found desirable to maintain the relative humidity within thecompartment at more than a certain minimum level, in order to minimizeand/or prevent unwanted electrostatic effects. Having regard to theaforesaid ranges, in such instances it is favorable to maintain arelative humidity (within the aforesaid ranges) at a level of about 20%or higher, more favorably 25% or higher, most favorably 30% or higher.For certain embodiments where the compartment may house a desiccator, insome instances it has been found desirable to pre-condition thedesiccant such that the initial relative humidity in the compartment isset at a particular desired value. For example it may be desirable thatthe set initial relative humidity is near the low end of the desiredand/or necessary relative humidity ranges, for example in the range ofabout 20% to about 30%, more favorably from about 25% to about 35%,still more favorably from about 30% to about 40%.

Preferably the compartment includes a single exit, i.e. the exit throughwhich the elongate carrier will be advanced is the only opening in thecompartment.

The compartment may be made by injection moulding a thermoplasticmaterial such as high density polyethylene or a cyclic olefin copolymer.In one embodiment, the supply spool (102) with elongate tape (100) andthe desiccator (108) may be loaded into the base of the compartment(105) and the tape threaded so that it is attached to the uptake spool(104). The compartment may then be closed by heat sealing a foillaminate lid (not shown) to the top of the compartment wall (106),thereby completely closing the compartment apart from at its exit (107).In an alternative configuration, the lid may be a molded plasticcomponent that is sealed onto the top of the compartment wall, e.g., byultrasonic welding, thermal welding, or adhesive bonding.

Desirably at least a part of, or most desirably all of, the walls of thecompartment are made of a material and/or are configured such that saidwall(s) provide a water vapor barrier. In particular it is desirablethat said wall(s) have a water vapor transmission rate (WVTR) less than12 g/(m² day) (38° C., 90% RH), more desirably a WVTR equal to or lessthan 6 g/(m² day) (38° C., 90% RH), even more desirably a WVTR equal toor less than 3 g/(m² day) (38° C., 90% RH), and most desirably a WVTRequal to or less than 1 g/(m² day) (38° C., 90% RH).

WVTR may be measured in accordance with a gravimetric method such asASTM E96/E96M-05, procedure E, desiccant method at 38° C./90% relativehumidity.

Favorably, at least a part of, or more favorably all of, the walls ofthe compartment are made of a material comprising a low water vapor(moisture) permeability material, in other words a vapor barriermaterial. A vapor barrier material can be described as a material that,when such material has a thickness of 100 microns, has a water vaportransmission rate (WVTR) less than 12 g/(m² day) (38° C., 90% RH), inparticular a WVTR equal to or less than 6 g/(m² day) (38° C., 90% RH);more particularly a WVTR equal to or less than 3 g/(m² day) (38° C., 90%RH); and most desirably a WVTR equal to or less than 1 g/(m² day) (38°C., 90% RH).

Said compartment wall(s) may be made of a single material (e.g., a vaporbarrier material) or alternatively a combination of materials (e.g.,different vapor barrier materials provided region-by-region or providedas a combination of layers in a wall, or alternatively vapor barriermaterial(s) in combination with other materials). As an example of thesecond mentioned alternative, the back wall and side walls may be madeof a polymeric vapor barrier material (such as high density polyethylene(HDPE)), and the front wall (lid) may be made of a metal foil (such asaluminum foil or a laminated foil comprising one or more metalliclayers). In another example the wall(s) of the compartment may be madeof two or more layers, each layer providing different impermeabilitycharacteristics. For example, for medicament that is sensitive tolong-term exposure to oxygen it may be favorable to use a material thatprovides desirable oxygen barrier characteristics (such as ethylenevinyl alcohol, nylon 6, nylon 66, polyvinylidene chloride, polyvinylacetate) in conjunction with a material that provides desirable vaporbarrier characteristics but typically does not provide favorable oxygenbarrier characteristics (such as high density polyethylene (HDPE)).Alternatively, wall(s) of the compartment may comprise two or morelayers e.g., for ease of manufacturing, and/or for stability. Forexample, wall(s) of the compartment may be made of an aluminum foillaminated to a suitable polymer layer or alternatively sandwichedbetween two appropriate polymer layers or alternatively aluminum may bedeposited onto an appropriate polymer layer (e.g., creating a metalizedpolyethylene terephthalate layer or metalized nylon layer) oralternatively two metalized plastic layers (e.g., aluminum deposited onpolyethylene or polypropylene) may be laminated together with themetalized surfaces facing each other. Another alternative is thelamination of a polymeric vapor barrier layer onto another polymericlayer inter alia for strength. In addition, wall(s) of the compartmentmay comprise an outer layer made of a vapor barrier material and aninner layer comprising a desiccant material. This could be done, forexample, using a two-shot molding process where the outer layer is apolymer with low vapor transmission rate (e.g., HDPE, polypropylene(PP), or a cyclic olefin copolymer) and the inner layer is a desiccatingpolymer (e.g., Nylon), or alternatively the outer layer could be made ofa polymeric vapor barrier material, whose interior surface is lined witha nonwoven embedded with desiccant particles. In regard to the latterthe material of the desiccant particles can be selected from theaforesaid list of materials. Additional examples of combinations includea blending of a vapor barrier material (e.g., PE) with another material(e.g., ethylene-vinyl acetate (EVA))

Suitable vapor barrier materials may include metal foil, in particularaluminum foil have a thickness of at least 8 microns, more particularlyat least 10 microns, even more particularly at least 15 microns, mostparticularly at least 25 microns. The desired and/or necessary thicknessdepends on how the foil is used. For example aluminum foil laminatedbetween layers of polymeric vapor barrier layers may only need to be 8microns thick, while for plain aluminum foil it may be desirable and/ornecessary to use a foil having a thickness of 25 microns or more. Thelid may desirably be 80 microns thick, including an aluminum foil layerof 8 microns sandwiched between layers of low density polyethylene andwith an outer coating of polyethylene terephthalate. Other suitablevapor barrier materials may include coatings, such as deposited aluminumcoatings (in particular having a thickness of at least 0.1 microns),deposited silicon oxide coatings (in particular having a thickness of atleast 0.04 microns), deposited diamond-like glass coatings (suchcoatings, and methods to produce such coatings, are described in U.S.Pat. No. 6,696,157 (David et al.) the content of which is incorporatedhere in its entirety). Further suitable vapor barrier materials mayinclude polymeric materials such as polyvinylchloride (hard orplasticized, in particular hard PVC); ethylene vinyl alcohol (inparticular ethylene vinyl alcohol having a high ethylene content, moreparticularly an ethylene content of at least 30%); polyacrylonitrile;polyethylene terephthalate; polyethylene naphthalate; polyolefins (inparticular polypropylene, copolymers of polypropylene with polyethylene,biaxially orientated polypropylene; polyethylene (including low densitypolyethylene (density equal to or less than 0.925 g/cm³)), linear lowdensity polyethylene, medium density polyethylene (density greater than0.925 g/cm³ and less than or equal to 0.94 g/cm³), high densitypolyethylene (density greater than 0.94 g/cm³); cyclic olefin copolymers(e.g., such as those commercially available under the trade designationTOPAS); poly-vinylidene chloride; polychlortrifluorethylene; and liquidcrystal polymers. Among polyethylenes, high density polyethylenes areparticularly advantageous as a vapor barrier material. Polymers, inparticular polyolefins (including low density polyethylene, linear lowdensity polyethylene, medium density polyethylene, high densitypolyethylene, polypropylene, biaxially orientated polypropylene)produced using metallocene catalysts are favorable in that the use ofsuch catalysts generally allows for the production of polymers havingnarrower molecular weight distributions than does the use of moretraditional Zeigler-Natta catalysts, and thus allows for a better,tighter control over composition and in turn vapor barriercharacteristics.

As applicable, walls of the compartment or parts of walls may beproduced via injection molding (e.g., single shot or multi-shot molding)as well as other methods including co-extrusion, extrusion lamination,vacuum metallization, or a combination of methods as desired and/orneeded.

It may be desirable, depending on the choice of wall material(s) and theparticular medicament(s), to provide at least a part of or, moredesirably all of, the walls of the compartment with a greater thicknessthan commonly used in such devices, without adding so much material asto make the device unwieldy. In particular, for wall materials that arenot foil-based (e.g., not metal-foil-based, nor polymer and metal-foillaminate based), it may be desirable to provide at least a part of, ormore desirably all of, the walls of the compartment with a thickness ofgreater than or equal to about 500 microns, more desirably greater thanor equal to about 1000 microns, most desirably greater than or equal toabout 1250 microns. It is also desirable to provide at least a part of,or more desirably all of, the walls of the compartment with a thicknessof less than or equal to 4 mm, more desirably less than or equal to 3mm, most desirably less than or equal to 2 mm.

As mentioned above the compartment may be favorably provided within acassette that is reversibly removable from the dry powder inhaler. Sucha cassette would favorably include also an uptake spool, so that theuser can easily insert the cassette into the dry powder inhaler and/oreasily remove the cassette. For long storage as an original and/or are-fill supply unit, the cassette may be sealed in a container, such asa pouch.

FIG. 7 is an illustration of the region about the compartment exit andthe lower portion of the chamber of the exemplary inhaler at the pointof actuation, i.e. where powder associated with the dose-release area isreleased from the carrier for inhalation by the patient through thepatient port.

Various means for releasing powder from an area of carrier independentof the patients' inspiratory effort are known. A number of such meansare disclosed in U.S. Pat. No. 5,619,984 (Hodson et al.), includingsystems providing mechanical effort, e.g., impaction, vibrations, gasflow etc., or electrostatically. The means for releasing powder from thecarrier during inhalation is favorably triggered in response to thepatient inhaling, in order to avoid the patient having to synchroniseactuation of the release mechanism with inhalation. Airflow detectionmay conveniently be accomplished by means of a movable vane positionedwithin the chamber or patient port, motion of the vane causing actuationof the release mechanism.

In the exemplary embodiment, the release of powder is triggered inresponse to the patient inhaling. In particular, upon inspiration by theuser a movable vane (not visible; an outer portion of a vane positioningpin (201) can be seen in FIGS. 1 to 3) within the chamber releases atrigger mechanism (not visible) that in turn releases a hammer (205;visible in FIGS. 4 to 7). The hammer then strikes the carrier (100), sothat the powder (90) associated with the dose-release area is releasedinto the chamber (200) (as illustrated in FIG. 7).

It has been found particularly advantageous to have the dose-releasearea of the carrier (i.e. that area of the portion of the carrier thathas been advanced to within the chamber for powder release) be clampedbetween a first and a second clamping system. As mentioned above, byclamping the area of the carrier to be impacted between two clampingsystems, during actuation, it is possible to reduce and/or preventpowder from other areas of the carrier (i.e. those areas either behindor ahead of the intended dose-release area) from being dislodged whenthe powder associated with the dose-release area is released. Thisadvantageously allows for improved reproducibility of the emitted dose.

The double clamping can be achieved by providing a first clamping systemand a second clamping system, wherein the first and second clampingsystems are configured and arranged such that they are moved into aclamping configuration at least prior to release of the powderassociated with the dose-release area, so that said area of the carrierwill be clamped between the first and the second clamping systems duringrelease of the powder associated with said area of the carrier. Asmentioned supra, an aspect of the present invention includes dry powderinhalers which include such a double clamping system, but do not makeuse of a moisture-barrier sealing system. Also as mentioned supra,certain embodiments in accordance with certain other aspects of thepresent invention include inhalers and/or cassettes including such adouble clamping system in addition to a moisture barrier sealing system.

For certain embodiments of inhalers and/or cassettes in accordance withthe present invention that include a moisture barrier sealing systemthat is configured and arranged such that the sealing system is returnedto its sealing configuration at least prior to release of the powderassociated with the dose-release area, the double clamping can beachieved in an alternative way, i.e. where the moisture barrier sealingsystem acts as a clamping system. Such embodiments would include aclamping system in addition to the moisture barrier sealing system, saidclamping system being configured and arranged such that it is moved intoa clamping configuration at least prior to release of the powderassociated with the dose-release area and wherein said clamping systemand said moisture barrier sealing system are configured and arrangedrelative to one another such that said dose-release area will be clampedbetween the clamping system and the moisture barrier sealing systemduring release of the powder associated with the dose-release area. Inother words the dose-release area is positioned between the moisturebarrier sealing system and a second clamping system and is clamped bythe two systems prior to dose release.

This latter alternative may be better appreciated by looking at theexemplary embodiment. As described in conjunction with FIGS. 4 to 6, themoisture barrier sealing system (110), in particular its seal (111), inits sealing configuration seals the exit (107) of the compartment (105)and at the same time clamps the carrier (100) against the wall (106) ofthe compartment (105), between the seal (111) and the outer surface (106a) of the compartment wall (106). See e.g., FIGS. 6 and 7 in comparisonto FIG. 5. So in the exemplary embodiment the moisture barrier sealingsystem also acts as a clamping system. The exemplary embodiment includesan additional clamping system (125), where in its clamping configuration(see again FIGS. 6, and 7 in comparison to FIG. 5), the carrier (100) isclamped via a grip (126) of the clamping system (125) against the outersurface (202 a) of the chamber wall (202). Referring to FIG. 7, it willbe appreciated that the area of carrier (100) that was advanced towithin the chamber (200) is clamped between the two systems. In thisembodiment the leading end of said area is clamped by the grip (126) ofthe clamping system and the trailing end by the seal (111) of themoisture barrier sealing system. When the hammer (205) strikes thecarrier (100) to release the powder (90) associated with the area of thecarrier that is positioned between the clamps, transfer of energy fromthat area of the carrier to other areas of the carrier (areas ahead orbehind the area of the carrier within the chamber that is intended fordose release when impaction by the hammer occurs) is minimized and/orprevented. In this manner, unwanted release of powder from areas of thecarrier still within the supply compartment (105) may be minimizedand/or prevented, as may unwanted release of any residual and/orremaining powder from areas of used carrier already in the uptake area.

In the exemplary embodiment, the second clamping system (125) is formedas an extension (118) of a pivoting component (112) that is used in themoisture barrier sealing system (110).

Here reference is made to FIGS. 8 to 11 showing a partialcross-sectional, detailed view (now without the cover) of the regionincluding the supply and uptake spools, compartment exit and flowchamber of the exemplary inhaler at closed (FIG. 8), partially open(FIG. 9), between partially & fully open (FIG. 10) and fully open (FIG.11) positions, respectively. (FIGS. 8, 9 and 11 correspond to FIGS. 1,2, and 3, respectively, as well as to FIGS. 4, 5 and 6, respectively.)

The pivoting component (112) has a front-plate (113) with a quasitriangular structure (see e.g., FIGS. 8 to 11) and a quasi-V-shaped ribback-structure (114) plus a pin-like structure (115) onto which the seal(111) is affixed (see FIGS. 4 to 7). One end of the aforementionedquasi-V-shaped rib back-structure (the one distal to the seal (111))provides the grip (126) of the clamping system. The other end isprovided in the form of a partial cylinder (116). The pivoting component(112) is held in place by a pin (not visible) that protrudes from theback of the partial cylinder (116), the pin being retained within asuitable cylindrical hole in the main frame or chassis of the inhalationdevice. The partial cylinder (116) is positioned within a “socket” inthe curve of the compartment wall (106). There is clearance between thepartial cylinder (116) and the “socket”, and as can be seen in theFigures the partial cylinder “rotates/pivots” in the “socket”. Moreover,comparing FIGS. 8 to 11 it can be seen that the pivoting component (112)pivots about an axis (P) generally perpendicular to the front-plate(113), the axis (P) falling within the partial cylinder (116) near butspaced apart from the seal (111). (Relative to the printed illustrationthe axis (P) is perpendicular to the page of the illustration and is tothe left and below the seal.)

As can be best seen in FIGS. 4 to 7 the exemplary embodiment includes apost (120) and a torsional spring (121). The post (120) is positionednear the quasi-V-shaped rib back-structure but on the far side relativeto the seal (111). The torsional spring (121) engages portions of theback-structure (114) of the pivoting component (112) and provides forceonto said pivoting component such that the seal (111) is biased towardsits sealing configuration, sealing off the exit (107) of the compartment(105). Comparing for example FIGS. 4 and 5, it can be recognized thatthe torsional spring (121) is providing a substantially counterclockwiseforce on to the pivoting component. The pivoting action of the pivotingcomponent is limited by providing a slot (117) in the front-platestructure and having one end of the post (120) extending through theslot. With reference to FIG. 8—the closed position of the exemplaryinhaler—the post (120) is located adjacent to the bottom of the slot(117), the seal (111) is sealing off the exit (107) and at the same timeclamping the carrier (100) against the outer surface of the compartment,and the portion of the carrier near and around (100 a) the uptake spool(104) is slack.

As the user opens the mouthpiece cover (301 in FIGS. 1 to 3) of theexemplary inhaler, as can be seen in FIG. 9—the partially open positionof the mouthpiece cover—the uptake spool turns in a clockwise directionand the outer turn of carrier about the uptake spool is drawn tight. Thenewly created tension of the carrier (100), and thus force, against theend of the upper extension/grip (118; visible in FIG. 9/126; not visiblein FIG. 9) of the pivoting component (112) (in particular against theend of the upper portion of the back structure, referred to above as thegrip (126)) overcomes the force from the torsional spring (121), thuscausing the pivoting component (112) to rotate in a substantiallyclockwise direction, and at the same time causing the moisture barriersealing system to relax (move out of its sealing configuration) therebycausing the exit (107) of the compartment (105) to be unsealed. Withreference to FIG. 9, the post (120) is adjacent to the top of the slot(117), the seal (111) has shifted slightly clockwise and downward, thecarrier is advancing over the seal (111) and over the grip (126, notvisible) and the uptake spool has rotated clockwise by about 90-100degrees from its illustrated position in FIG. 8 to its illustratedposition in FIG. 9. The latter is best seen and understood throughreference to the movement of a quasi-semi-circular cam feature (145) onthe forward ratchet (144) on the uptake spool (104), which indicatesthat said uptake spool has rotated clockwise by about 90-100 degrees.

As the user continues to open the mouthpiece cover (301) of theexemplary inhaler to a position between partially open and fully open—ascan be seen in FIG. 10—the uptake spool continues to turn in a clockwisedirection and the aforementioned cam (145) on the forward ratchet (144)begins to engage a heel (119) of the pivoting component (112), therebyurging the pivoting component to rotate/pivot counter-clockwise andmoving the grip (126) of the clamping system (125) towards the chamberwall (202). Finally as the user opens the mouthpiece cover (301)completely (to the fully open position as illustrated in FIG. 11), thegrip (126) of the clamping system (125) is at last fully engaged withthe carrier (100)/chamber wall (202) (i.e. clamping the carrier (100)against the outer surface (202 a) of the chamber wall (202)) and theseal (111) of the moisture barrier system is engaged with the carrier(100)/compartment wall (106) (i.e. clamping the carrier (100) againstthe outer surface (106 a) of the compartment wall (106)), so that thedose-release area is clamped between the seal (111) and the grip (126).The presence of an elastomeric seal (111) in the moisture barriersealing system (110) enables this seal (111) to seal against the surface(106 a) of the compartment wall (106) before the grip (126) of theclamping system (125) fully seals against the surface (202 a) of thechamber wall (202). The use of cam (145) and its engagement against theheel (119) of the pivoting component (112) facilitates the sealing ofthe grip (126) against the chamber wall (202). The exemplary inhaler isnow ready for release of the powder associated with the dose-releasearea (said release already having been described in conjunction withFIG. 7).

In alternative embodiments, the pivoting component (112) may besubstituted by a component that moves linearly to clamp and unclamp thecarrier, said component being located and arranged in any suitablemanner that will be apparent to one skilled in the art who has studiedthe present disclosure and exemplary embodiment.

A clamping system may comprise a grip or grips. Desirably such grip(s)have a form and comprise a material suitable for appropriately clampingthe carrier. Suitable materials for a clamping system grip may have aShore A hardness equal to or less than 85, in particular equal to orless than 75 (as determined by ASTM test number D2249). Suitablematerials for a clamping system grip may have a Shore A hardness equalto or greater than 35, in particular equal to or greater than 45 (asdetermined by ASTM test number D2249). A grip may be made of the samematerial as another (e.g., pivoting) component, so that it is contiguouswith that component. Alternatively, a grip may comprise an elastomericmaterial, e.g., an elastomeric grip component affixed to the pivotingcomponent in much the same way as the moisture barrier seal is affixedto the pivoting component. As other options, the grip may be 2-shotmolded to the pivoting component. Since it is believed that one of thefunctions of the double clamping is to prevent or reduce vibrations ofthe carrier, by absorbing some or all of their energy, which occurduring release of powder from the dose-release area, from beingtransferred to regions of the carrier outside the dose-release area,this may be facilitated by using an elastomeric material (in particularsuch a material having a lower Shore A hardness value e.g., around 35 to55) for both the grip(s) and the seal of moisture barrier sealingsystem, as applicable. Increasing the distance along the area of thecarrier that the clamps operate could be more effective in damping.However such parameters would need to be optimized with otherperformance considerations for the device, e.g., disturbance of powderby contact with the clamps and/or the need to advance lengths of carriermuch longer than the length of the dose-release area.

In particularly favorable embodiments of devices in accordance withcertain aspects described herein the moisture barrier sealing system isconfigured and arranged such that the sealing system is returned to itssealing configuration upon cessation of advancement of the carrier. Thegeneral functioning of such particularly favorable embodiments may be asfollows: whenever the patient is advancing the carrier by exerting forceon a user-operated advancing element (such as by pulling/holding themouthpiece-cover open in the exemplary inhaler; alternativeuser-operated advancing elements may include buttons or levers), thecarrier is placed under tension (part of said patient-exerted force istransmitted via appropriate device components into tension in thecarrier), said tension causing the moisture barrier sealing system todisengage, opening the compartment exit thereby allowing carrier to passeasily through the exit. Upon cessation of advancement of the carrier(in other words as soon as the patient ceases to exert force on theuser-operated advancing element), the tension in the carrier is relievedor reduced and the carrier goes slack, causing the moisture barriersealing system to return to its sealing position (e.g., under its ownaccord (e.g., due to elastic resilience) or under the influence of aseparate component (such as a torsional spring (as in the exemplaryinhaler)). Such embodiments are particular advantageous in that themedicament supply compartment is only un-sealed wherever it is needed toadvance the carrier, and sealed whenever it does not need to be unsealedto allow tape advance, said sealing and unsealing being “automatic” andnot compromised by forgetfulness nor confusion on the part of thepatient. Additional benefits of such a sealing arrangement are thatwhenever tape is not being advanced the medicament supply compartment isprotected against moisture ingress from the exhaled breath if that isinadvertently exhaled into the inhaler device, and also that any drugpowder that may come loose from the supply of tape cannot escape fromthe medicament supply compartment.

In the exemplary inhaler described herein, the moisture barrier sealingsystem, in particular the seal thereof, is favorably coupled to apivoting member that is engaging a spring, said spring urging thepivoting member in a direction such that the moisture barrier seal sealsthe compartment exit, and wherein upon advancement of the carrier underthe tension associated with the advancement of the carrier the pivotingmember rotates in the opposite direction, so that the moisture barrierseal disengages, opening the compartment exit thereby allowing carrierto advance through the exit, and upon cessation of advancement of thecarrier, under the tension of the spring the pivoting member rotates inits original direction, so that the moisture barrier seal seals thecompartment exit.

FIG. 12 shows a sealed position of the exemplary inhaler reached by auser who has stopped advancing the carrier (i.e. who has stoppedpulling/holding the mouthpiece-cover (301) open) after having advancedit partially. Upon letting go of the mouthpiece-cover, the tension inthe carrier (100) has caused the mouthpiece-cover (301), forward ratchetand uptake spool (104) to rotate counter-clockwise by about 10 degreesor so. This back rotation relieves tension in the carrier (100) andcreates enough slack in it for the pivoting component (112) to rotatecounter-clockwise under the force of the torsional spring (121) untilthe seal (111) of the moisture barrier sealing system re-engages withthe compartment wall (106) and thus re-seals the exit slot (107) of thecompartment (105).

As mentioned above, the elongate carrier may be wound on a spool withinthe supply compartment. It is desirable that the spool comprises ananti-unspooling mechanism. An anti-unspooling mechanism, which couldutilize a friction brake, a ratchet system, or some other mechanism toprevent unspooling of the carrier, desirably reduces or prevents anyrotation of the supply spool not associated with advancement of thecarrier. An anti-unspooling mechanism also favorably provides resistanceto movement of the elongate carrier while it is being advanced, inparticular just after the moisture barrier sealing system has relaxed.This resistance to movement facilitates the creation/maintenance oftension in the carrier during advancement of the carrier.

Such a mechanism may be best understood by reference to FIGS. 13 and 14,providing an isometric view of part of the compartment of the exemplarydry powder inhaler, showing the supply spool and the anti-unspoolingmechanism, in particular a friction brake, and a partial cross sectionalillustration of the region of the supply spool with elongate carrierwound on it, plus the outer component of the friction brake,respectively.

The supply spool (102) has the elongate carrier (100), preloaded withfinely divided powder wound thereon. As can be seen from FIGS. 13 and14, the lower part of the supply spool has an annular flange (151) toretain the carrier and a cylindrical core (152) around which theelongate carrier is wound. The compartment (105) has a supply post (153)which provides an axle for the supply spool (102) to rotate about. Thesupply post is generally cylindrical, with a smooth surface. As analternative, the surface of the supply post may be splined, with splinesarranged uniformly about the circumference directed parallel to theaxis. The interior (155) of the cylindrical core has an inwardlyupwardly directed lip (156) extending from about half way up andarranged to contact the supply post to provide an interference withfrictional properties at the contact region (157). The lip has twodiametrically opposite wide slits (158 a,b) extending from the contactregion (157) part of the way back to the cylindrical core (152). Theseslits allow the lip to pull away from the supply post slightly under theinfluence of the interference fit, but be retained by the elasticproperties of the supply spool material. Where the supply post issplined, the contact region of the lip may also have splines. The twosets of splines allow the supply spool to rotate on the supply post onlywhen the post splines push the spool splines back a small amount,causing the spool to click round in defined small increments during use.The friction brake is provided by the interference in the contact region(157) and ensures that the elongate carrier remains tightly wound on thesupply spool during use.

Finely divided powders used in the devices described herein generallyhave a mass median particle diameter typically 10 microns or less. Moresuitably, said mass median diameter is 7 microns or less, even moresuitably 5 microns or less, and most suitably said mass median diameteris in the range 1 to 3 microns, with at least 90% by mass of theparticles having diameters below 5 microns.

The powders may be micronized, e.g., by using a fluid energy mill drivenby compressed air, such as shown in ‘Drug Delivery to the RespiratoryTract’ ed. D. Ganderton and T. Jones, publ. Ellis Horwood, Chichester(1987) pages 89-90, or by repeated stepwise millings or by use of aclosed loop milling system.

As indicated supra, desirably finely divided powder is filled into aplurality of microdepressions in the surface of an elongate carrier, inparticular a flexible elongate carrier, such as a web or a tape.Depressions may be suitably spaced at an interval of about 20 to 2000microns, more suitably at an interval of about 300 to 2000 microns.Depressions may suitably number from about 25 to 1000 per cm² of thecarrier. The volume of each depression and the spacing or number of thedepressions will depend upon the particular desired application of theresulting filled elongate carrier, and in the case of biologicallyactive substances (e.g., medicaments) the potency of the particularsubstance and the area of the carrier material intended to provide asingle dose of the substance. Typically it is desirable that the carriermaterial has a substantially uniform depression volume per unit areawhen considered on a scale of the area of a single dose or otherfunctional unit. For example, such a dose area might have 200 to 2000discrete microdepressions, each of about 45 microns depth and about 150microns diameter. Advantageously, the rows of microdepressions along thelongitudinal axis of the elongate carrier do not lie exactly parallelwith the axis, but instead lie skewed at a small angle (e.g., 0.5° to2°) to it, in order to avoid “quantization effects” caused by lateralvariability in the slitting positions. (The skew angle can be chosenappropriate to the microdepression spacing distance and the desired slitwidth, such that an exact total microdepression volume is present oneach (e.g., 20 mm×10 mm) dose area, no matter where slitting occurs,laterally.) Preferably, the microdepressions are provided by castembossing of a low density polyethylene (LDPE) layer using aphotolitho-graphically patterned and etched, or a diamond machined,patterning roller. Suitably the aforesaid LDPE layer is provided on apaper backing or a paper/LDPE laminate backing (with the paper betweenthe two LDPE layers).

Such filled elongate carriers are particularly conveniently be used inthe administration of biologically active substances, in particularmedicaments by inhalation. Moreover, elongate carriers havingmicrodepressions can be substantially accurately and uniformly filledwith such finely divided powders e.g., through methods disclosed in WO2007/112267 (Hodson and Wilby) (the content of which is incorporated inits entirety by reference), thus allowing for accurate and uniformrelease of doses of biologically active substances.

For delivery by inhalation, suitable medicaments include any drug ordrug combination that may be administered by inhalation, that is a solidor that may be incorporated in a solid carrier. Suitable drugs includethose for the treatment of respiratory disorders, e.g., bronchodilators,anti-inflammatories (e.g., corticosteroids) anti-allergics,anti-asthmatics, anti-histamines, and anti-cholinergic agents. Otherdrugs such as anorectics, anti-depressants, anti-hypertensive agents,anti-neoplastic agents, anti-tussives, anti-anginals, anti-infectives(e.g., antibacterials, antibiotics, anti-virals), anti-migraine drugs,anti-peptics, dopaminergic agents, analgesics, beta-adrenergic blockingagents, cardiovascular drugs, hypoglaecemics, immunomodulators, lungsurfactants, prostaglandins, sympathomimetics, tranquilizers, steroids,vitamins and sex hormones, vaccines and other therapeutic proteins andpeptides may be employed for delivery by inhalation.

It is preferred for delivery by inhalation that the medicament employedexhibits a potency which permits a single dose to be loaded onto theelongate carrier in an area of less than about 25 cm² and preferablyless than about 5 cm². More preferred is an elongate carrier containinga drug in such a manner and of such a type that between 0.25 and 2.5cm², most preferably between 1.5 and 2.25 cm², of the elongate carrierwill contain a single dose when used in a device such as those describedin U.S. Pat. No. 5,408,994 or 5,619,984. Stated differently, given thata filled elongate carrier may conveniently carry between about 25 and500 μg of powder per cm², the potency of the medicament will preferablybe such that a single dose may be carried on the above-stated 0.25 to2.5 cm² of elongate carrier.

Exemplary drugs which may be employed for delivery by inhalation includebut are not limited to: albuterol, levalbuterol, terbutaline, fenoterol,metaproterenol, isoproterenol, isoetharine, bitolterol, epinephrine,tulobuterol, bambuterol, reproterol, adrenaline, ipratropium,oxitropium, tiotropium, daratropium, aclidinium, glycopyrronium,beclomethasone, butixocort, betamethasone, flunisolide, budesonide,mometasone, ciclesonide, rofleponide, aminophylline, dyphylline,theophylline, cromolyn sodium, nedocromil sodium, ketotifen, azelastine,ergotamine, cyclosporine, salmeterol, fluticasone, formoterol,arformoterol, procaterol, indacaterol, TA2005 (carmoterol), omalizumab,montelukast, zafirlukast, betamethasone sodium phosphate, dexamethasone,dexamethasone sodium phosphate, dexamethasone acetate, prednisone,methylprednisolone acetate, oglemilast, zileuton, insulin, atropine,prednisolone, benzphetamine, chlorphentermine, amitriptyline,imipramine, clonidine, actinomycin c, bromocriptine, fentanyl,buprenorphine, pentamidine, calcitonin, leuprolide, alpha-1-antitrypsin,interferons, human growth hormones, propranolol, lacicortone,triamcinolone, dinoprost, xylometazoline, diazepam, lorazepam, folicacid, nicotinamide, clenbuterol, ethinyloestradiol, levonorgestrel, andpharmaceutically acceptable salts and esters thereof such as albuterolsulfate, formoterol fumarate, salmeterol xinafoate, aclidinium bromide,glycopyrronium bromide, beclomethasone dipropionate, triamcinoloneacetonide, fluticasone propionate, fluticasone furoate, tiotropiumbromide, leuprolide acetate and mometasone furoate.

Further drugs that may also be delivered by inhalation include but arenot limited to aspirin, acetaminophen, ibuprofen, naproxen sodium,buprenorphine hydrochloride, propoxyphene hydrochloride, propoxyphenenapsylate, meperidine hydrochloride, hydromorphone hydrochloride,morphine sulfate, fentanyl citrate, oxycodone hydrochloride, codeinephosphate, dihydrocodeine bitartrate, pentazocine hydrochloride,hydrocodone bitartrate, levorphanol tartrate, diflunisal, naltrexone,oxycodone, sufentanil, remifentanil, diamorphine, trolamine salicylate,methadone hydrochloride, nalbuphine hydrochloride, nalorphine,tetrahydrocannabinol, mefenamic acid, butorphanol tartrate, cholinesalicylate, butalbital, phenyltoloxamine citrate, diphenhydraminecitrate, methotrimeprazine, cinnamedrine hydrochloride, meprobamate,ergotamine tartrate, propanolol hydrochloride, isometheptene mucate,dichloralphenazone, sumatriptan, rizatriptan, zolmitriptan, naratriptan,eletriptan, barbiturates (e.g., pentobarbital, pentobarbital sodium,secobarbital sodium), benzodiazapines (e.g., flurazepam hydrochloride,triazolam, tomazeparm, midazolam hydrochloride, lorazepam, buspironehydrochloride, prazepam, chlordiazepoxide hydrochloride, oxazepam,clorazepate dipotassium, diazepam, temazepam), lidocaine, prilocaine,xylocaine, beta-adrenergic blockers, calcium channel blockers (e.g.,nifedipine, diltiazem hydrochloride, and the like), diuretics (e.g.,amiloride, furosemide), nitrates (e.g., nitroglycerin, isosorbidedinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate),hydroxyzine pamoate, hydroxyzine hydrochloride, alprazolam, droperidol,halazepam, chlormezanone, haloperidol, loxapine succinate, loxapinehydrochloride, thioridazine, thioridazine hydrochloride, thiothixene,fluphenazine hydrochloride, fluphenazine decanoate, fluphenazineenanthate, trifluoperazine hydrochloride, chlorpromazine hydrochloride,perphenazine, lithium citrate, prochlorperazine, lithium carbonate,bretylium tosylate, esmolol hydrochloride, verapamil hydrochloride,amiodarone, encainide hydrochloride, digoxin, digitoxin, mexiletinehydrochloride, disopyramide phosphate, procainamide hydrochloride,quinidine sulfate, quinidine gluconate, quinidine polygalacturonate,flecainide acetate, tocainide hydrochloride, lidocaine hydrochloride,phenylbutazone, sulindac, penicillamine, salsalate, piroxicam,azathioprine, indomethacin, meclofenamate sodium, gold sodiumthiomalate, ketoprofen, auranofin, aurothioglucose, tolmetin sodium,colchicine, allopurinol, heparin, heparin sodium, warfarin sodium,urokinase, streptokinase, altoplase, aminocaproic acid, pentoxifylline,empirin, ascriptin, valproic acid, divalproate sodium, phenytoin,phenytoin sodium, clonazepam, primidone, phenobarbitol, phenobarbitolsodium, carbamazepine, amobarbital sodium, methsuximide, metharbital,mephobarbital, mephenytoin, phensuximide, paramethadione, ethotoin,phenacemide, secobarbitol sodium, clorazepate dipotassium,trimethadione, ethosuximide, doxepin hydrochloride, amoxapine, trazodonehydrochloride, amitriptyline hydrochloride, maprotiline hydrochloride,phenelzine sulfate, desipramine hydrochloride, nortriptylinehydrochloride, tranylcypromine sulfate, fluoxetine hydrochloride,doxepin hydrochloride, imipramine hydrochloride, imipramine pamoate,nortriptyline, amitriptyline hydrochloride, isocarboxazid, desipraminehydrochloride, trimipramine maleate, protriptyline hydrochloride,hydroxyzine hydrochloride, diphenhydramine hydrochloride,chlorpheniramine maleate, brompheniramine maleate, clemastine,azelastine, cyproheptadine hydrochloride, terfenadine citrate,loratidine, clemastine, triprolidine hydrochloride, carbinoxaminemaleate, diphenylpyraline hydrochloride, phenindamine tartrate,lamivudine, abacavir, acyclovir, gancyclovir, valganciclovir, cidofovir,foscarnet, azatadine maleate, tripelennamine hydrochloride,dexchlorpheniramine maleate, methdilazine hydrochloride, trimprazinetartrate, trimethaphan camsylate, phenoxybenzamine hydrochloride,pargyline hydrochloride, deserpidine, diazoxide, guanethidinemonosulfate, minoxidil, rescinnamine, sodium nitroprusside, rauwolfiaserpentina, alseroxylon, phentolamine mesylate, reserpine, calcitonin,parathyroid hormone, acitretin, amikacin sulfate, aztreonam,benzydamine, calcipotriol, chloramphenicol, chloramphenicol palmitate,chloramphenicol sodium succinate, ciprofloxacin hydrochloride,clindamycin hydrochloride, clindamycin palmitate, clindamycin phosphate,efalizumab, reslizumab, mepolizumab, anrukinzumab, metronidazole,metronidazole hydrochloride, gentamicin sulfate, lincomycinhydrochloride, tobramycin sulfate, tacrolimus, vancomycin hydrochloride,polymyxin B sulfate, colistimethate sodium, colistin sulfate,tetracycline, griseofulvin, keloconazole, interferon gamma, zidovudine,amantadine hydrochloride, ribavirin, acyclovir, pentamidine e.g.,pentamidine isoethionate, cephalosporins (e.g., cefazolin sodium,cephradine, cefaclor, cephapirin sodium, ceftizoxime sodium,cefoperazone sodium, cefotetan disodium, cefutoxime axotil, cefotaximesodium, cefadroxil monohydrate, ceftazidime, cephalexin, cephalothinsodium, cephalexin hydrochloride monohydrate, cefamandole nafate,cefoxitin sodium, cefonicid sodium, ceforanide, ceftriaxone sodium,ceftazidime, cefadroxil, cephradine, cefuroxime sodium, and the like),penicillins (e.g., ampicillin, amoxicillin, penicillin G benzathine,cyclacillin, ampicillin sodium, penicillin G potassium, penicillin Vpotassium, piperacillin sodium, oxacillin sodium, bacampicillinhydrochloride, cloxacillin sodium, ticarcillin disodium, azlocillinsodium, carbenicillin indanyl sodium, penicillin G potassium, penicillinG procaine, methicillin sodium, nafcillin sodium, and the like),erythromycins (e.g., erythromycin ethylsuccinate, erythromycin,erythromycin estolate, erythromycin lactobionate, erythromycin siearate,erythromycin ethylsuccinate, and the like), tetracyclines (e.g.,tetracycline hydrochloride, doxycycline hyclate, minocyclinehydrochloride, GM-CSF, ephedrine, pseudoephedrine, ammonium chloride,androgens (e.g., danazol, testosterone cypionate, fluoxymesterone,ethyltostosterone, testosterone enanihate, methyltestosterone,fluoxymesterone, testosterone cypionate), estrogens (e.g., estradiol,estropipate, conjugated estrogens), progestins (e.g.,methoxyprogesterone acetate, norethindrone acetate), levothyroxinesodium, human insulin, purified beef insulin, purified pork insulin,glyburide, chlorpropamide, glipizide, tolbutamide, tolazamide,rosiglitazone, pioglitazone, troglitazone, clofibrate, dextrothyroxinesodium, probucol, lovastatin, rosuvastatin, niacin, DNase, alginase,superoxide dismutase, lipase, calcitonion, alpha-1-antitrypsin,interferons, sense or anti-sense nucleic acids encoding any proteinsuitable for delivery by inhalation, erythropoietin, famotidine,cimetidine, ranitidine hydrochloride, omeprazole, esomeprazole,lanzoprazole, meclizine hydrochloride, nabilone, prochlorperazine,dimenhydrinate, promethazine hydrochloride, thiethylperazine,scopolamine, sildenafil, vardenafil, cilomilast, imiquimod orresiquimod. Where appropriate, these drugs may be delivered inalternative salts forms.

The medicament may comprise one or more drugs, having one or moreparticulate forms, and may include one or more physiologicallyacceptable or inert excipients.

1. A storage device for storing dry powder for use in a dry powderinhaler, the device comprising: an elongate carrier preloaded with aplurality of doses of finely divided powder comprising a biologicallyactive substance, the powder being releasably retained on a surface ofthe carrier; a first clamping system and a second clamping system,wherein the device is configured and arranged such that during use in adry powder inhaler wherein a portion of the carrier is advanced so thatthe powder associated with an advanced area can be released from thecarrier for inhalation by the patient through the patient port of theinhaler, the first and second clamping systems will be moved into aclamping configuration at least prior to release of the powderassociated with the area of the carrier, so that the area of the carrierwill be clamped between the first and the second clamping systems duringrelease of the powder associated with the area of the carrier, andwherein the device further comprises a moisture barrier sealing system,wherein the device is configured and arranged such that during use in adry powder inhaler, the first and second clamping systems are movable,the clamping systems being moved into a clamping configuration at leastprior to release of the powder associated with the area of the carrierand such that the area of the carrier will be clamped between the firstand second clamping systems and the moisture barrier sealing systemduring release of the powder associated with the area of the carrier. 2.The storage device of claim 1, wherein the clamping system is configuredand arranged so that when the carrier is being advanced, the first andsecond clamping systems are out of their clamping configuration.
 3. Thestorage device of claim 2, wherein the moisture barrier sealing systemcomprises a seal.
 4. The storage device of claim 3, wherein the sealcomprises a material having a Shore A durometer value equal to or lessthan 75 and equal to or greater than 35; and wherein the seal comprisesan elastomeric material, selected from the group consisting of siliconerubber, EPDM, polypropylene blends, styrene-isoprene copolymers,combinations and mixtures thereof.
 5. The storage device of claim 4,wherein the moisture barrier sealing system comprises a seal coupled toa moveable member that is engages with a spring, the spring urging themoveable member in a first direction such that the moisture barrier sealseals the compartment exit, and wherein upon advancement of the carrierunder the tension associated with the advancement of the carrier themoveable member moves in the opposite direction, so that the moisturebarrier seal disengages, and wherein upon cessation of advancement ofthe carrier, the moveable member moves in its original direction underthe force of the spring, so that the moisture barrier seal creates aseal, in particular wherein the movement of the moveable membercomprises a substantially rotational or linear movement.
 6. The storagedevice of claim 1, wherein the device is configured to be inserted intothe dry powder inhaler.
 7. The storage device of claim 1, wherein thestorage device is removable from the dry powder inhaler.